Beraprost is a synthetic benzoprostacyclin analogue of natural prostacyclin consisting of four isomers (Beraprost-314d, Beraprost-314d's enantiomer, Beraprost-315d and Beraprost-315d's enantiomer), as shown in Scheme A. Among them, optically pure Beraprost-314d (termed as Esuberaprost, APS-314d or BPS-314d) is the pharmacologically active isomer, and is currently under clinical trials as an added-on active pharmaceutical ingredient in the inhaled treprostinil (Tyvaso®) for the treatment of diseases, such as pulmonary arterial hypertension in North America and Europe. The preparation of Beraprost-314d has been previously described, e.g., in Heterocycles, 2000, 53, 1085-1092, U.S. Pat. No. 8,779,170, and WO 2017/174439.

A stable solid form of Beraprost-314d crystal can be widely used in storage, shipment, and handling for commercial considerations. Additionally, a stable Beraprost-314d crystal having fixed physicochemical properties can provide constant operating parameters, e.g., solubility for regular pharmaceutical formulation and steady bioabsorbability for pharmacological treatment. WO 2017/174439 discloses a crystalline form of Beraprost-314d (termed as Form I). However, it does not disclose the stability data of Beraprost-314d crystal Form I, so it is uncertain whether there exists a crystalline form transformation for Beraprost-314d crystal Form I or not. Thus, the benefits of the conventional crystallization methods for preparing a stable Beraprost-314d crystal cannot be evaluated based on the prior art reference.
Consequently, there is a demand for crystallization methods for the preparation of a stable solid form of Beraprost-314d crystal in an efficient and economical way where the novel Beraprost-314d crystal form can remain stable when stored at room temperature for commercial use.